Michael L. Hancock

Acute Myeloid Leukemia in Children Treated with Epipodophyllotoxins for Acute Lymphoblastic Leukemia

BACKGROUND AND METHODS Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration. RESULTS Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined. CONCLUSIONS The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.

Low Leukocyte Counts with Blast Cells in Cerebrospinal Fluid of Children with Newly Diagnosed Acute Lymphoblastic Leukemia

BACKGROUND Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial. METHODS The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, or cranial-nerve palsy; they received additional intrathecal injections of chemotherapeutic agents and cranial irradiation. Patients were retrospectively classified on the basis of cerebrospinal fluid findings: 291 patients had no detectable blast cells, 42 had fewer than 5 leukocytes per microliter and blast cells, and 18 had central nervous system leukemia as defined above. The clinical characteristics and outcomes of treatment in these groups were analyzed. RESULTS The five-year probability of survival free of relapses confined to the central nervous system in patients with detectable blast cells and fewer than 5 leukocytes per microliter of cerebrospinal fluid was lower than in patients without blast cells (mean [+/- SE], 87 +/- 13 vs. 96 +/- 2 percent), but was not different from the probability in patients with central nervous system leukemia at diagnosis. All such isolated relapses of leukemia in patients with detectable blast cells occurred during the first year of treatment, before scheduled cranial irradiation. In a multivariate analysis, the presence of cerebrospinal fluid blast cells with fewer than 5 leukocytes per microliter was independently related to the risk of relapse confined to the central nervous system. CONCLUSIONS Patients with leukemic blast cells in their cerebrospinal fluid are at increased risk for central nervous system relapse when cranial irradiation is delayed. Such patients require intensified central nervous system treatment early in the course of therapy.

Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia

BACKGROUND Recombinant human granulocyte colony-stimulating factor PO1 CA-20180ilgrastim) hastens the recovery from neutropenia after P30 CA-21765emotherapy, but its role in the management of childhood leukemia is unclear. METHODS We randomly assigned 164 patients with acute lymphoblastic leukemia (age range, 2 months to 17 years) to receive placebo or G-CSF (10 microg per kilogram of body weight per day subcutaneously), beginning one day after the completion of remission-induction therapy and continuing until the neutrophil count was greater than or equal to 1000 per cubic millimeter for two days. The clinical and laboratory effects of this therapy were documented for 21 days. The area under the plasma G-CSF concentration-time curve was measured on days 1 and 7 in both groups. RESULTS Responses to the growth factor could be assessed in 148 patients (73 in the G-CSF group and 75 in the placebo group). G-CSF treatment did not significantly lower the rate of hospitalization for febrile neutropenia (58 percent in the G-CSF group vs. 68 percent in the placebo group; relative risk, 0.85; 95 percent confidence interval, 0.59 to 1.16), increase the likelihood of event-free survival at three years (83 percent in both groups), or decrease the number of severe infections (five in the G-CSF group vs. six in the placebo group). Patients treated with G-CSF had shorter median hospital stays (6 days vs. 10 days, P=0.011) and fewer documented infections (12 vs. 27, P=0.009). The median total costs of supportive care were similar in the G-CSF and placebo groups (

Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium report

8,768 and

Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome.

8,616, respectively). Among patients who did not have febrile neutropenia during the first week of G-CSF or placebo injections, higher systemic exposure to the growth factor on day 7 was significantly related to a lower probability of subsequent hospitalization (P=0.049). CONCLUSIONS G-CSF treatment had some clinical benefit in children who received induction chemotherapy for acute lymphoblastic leukemia, but it did not reduce the rate of hospitalization for febrile neutropenia, prolong survival, or reduce the cost of supportive care.

Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.

Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative.

We developed a stroma cell culture system that suppresses apoptosis of malignant cells from cases of B-lineage acute lymphoblastic leukemia. By multiparameter flow cytometric measurements of cell recovery after culture on stromal layers, we assessed the growth potential of 70 cases of newly diagnosed B-lineage acute lymphoblastic leukemia and related the findings of treatment outcome in a single program of chemotherapy. The numbers of leukemic cells recovered after 7 d of culture ranged from < 1 to 292% (median, 91%). The basis of poor cell recoveries from stromal layers appeared to be a propensity of the lymphoblasts to undergo apoptosis. The probability of event-free survival at 4 yr of follow-up was 50 +/- 9% (SE) among patients with higher cell recoveries ( > 91%), and 94 +/- 6% among those with reduced cell recoveries (+/- 91%; P = 0.0003). The prognostic value of leukemic cell recovery after culture exceeded estimates for all other recognized high-risk features and remained the most significant after adjustment with all competing covariates. Thus, the survival ability of leukemic cells on bone marrow-derived stromal layers reflects aggressiveness of the disease and is a powerful, independent predictor of treatment outcome in children with B-lineage acute lymphoblastic leukemia.

Reappraisal of the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-ML) are serious complications that affect some patients after acute lymphoblastic leukemia (ALL) treatment. Genetic polymorphisms in the promoter of CYP3A4 (CYP3A4*1B) and in NAD(P)H:quinone oxidoreductase (NQO1609C-->T substitution) have been associated with the risk of t-ML. A polymorphism in CYP3A5 (CYP3A5*3) affects CYP3A activity and the wild-type allele (CYP3A5*1) is in partial linkage with the CYP3A4*1B allele. We compared the genotype frequencies for the CYP3A5*3, the CYP3A4*1B and the NQO1609C-->T substitution in 224 children with ALL who did not develop t-ML (controls) and in 53 children with ALL who did develop the complication. The allele frequencies differed significantly among whites, blacks and Hispanics (P < 0.001 for CYP3A5*3, P < 0.001 for CYP3A4*1B and P = 0.004 for NQO1609), thus we performed the comparisons between ALL controls and t-ML patients after accounting for race. We found no differences in the CYP3A4*1B allele distribution between ALL controls and t-ML patients in whites (P = 0.339, 6.6% vs. 9.8%), blacks (P = 0.498, 93.8% vs. 87.5%) or Hispanics (P = 0.523, 39.1% vs. 25.0%). The frequencies for the NQO1609C-->T allele did not differ between control and t-ML groups in whites (P = 0.191, 35.0% vs. 44.9%), blacks (P = 0.664, 37.5% vs. 37.5%) or Hispanics (P = 0.447, 65.2% vs. 50.0%). We found no differences between the control and t-ML group in the incidence of homozygous CYP3A5*3 genotypes: 82.0% vs. 85.4% in whites (P = 0.403), 6.5% vs. 12.5% in blacks (P = 0.508), and 69.6% vs. 75.0% in Hispanics (P= 0.663). Our data do not support an association between common CYP3A4, NQO1 or CYP3A5 polymorphisms and the risk of t-ML in children treated for ALL.

TMPRSS2:ERG Gene Fusion Predicts Subsequent Detection of Prostate Cancer in Patients With High-Grade Prostatic Intraepithelial Neoplasia

PURPOSE To evaluate the immunophenotypes, karyotypes, and clinical features, including treatment responses, of patients with childhood acute lymphoblastic leukemia (ALL) and either a t(1;19)(q23;p13) or a der(19)t(1;19)(q23;p13) translocation. PATIENTS AND METHODS The lymphoblasts of 45 patients with a balanced translocation, t(1;19) or its derivative form, der(19)t(1;19), were analyzed by cytogenetic and immunologic methods for differences that might suggest distinct subtypes of ALL. This cohort was treated in four consecutive clinical trials with a median overall follow-up duration of 7 years. RESULTS A pre-B immunophenotype was found in 10 cases with the balanced t(1;19) and 31 with the unbalanced der(19)t(1;19). The four remaining cases, each with a derivative t(1;19), were classified as early pre-B ALL. The characteristic surface antigen profile of the 41 pre-B cases was CD19+/CD10+/CD22+/CD34-/CD20+/-, whether the translocation was balanced or derivative. In contrast to the four early pre-B cases, which had hyperdiploid karyotypes (> 50 chromosomes), the pre-B cases were primarily pseudodiploid. Comparison of presenting clinical and laboratory features, as well as event-free survival, failed to disclose any differences that would warrant separation of pre-B cases with a balanced or derivative translocation. However, neither subgroup responded to therapy as well as patients with early pre-B ALL, each of whom remains in complete remission for > or = 3 years. CONCLUSION The t(1;19) and the der(19)t(1;19) identify a relatively homogeneous group of patients with pre-B ALL, who can be expected to respond similarly to intensive chemotherapy. The exceptional cases have an early pre-B phenotype with hyperdiploid karyotypes and appear to have favorable prognosis.

Prostate Cancer Diagnosis Among Men With Isolated High-Grade Intraepithelial Neoplasia Enrolled Onto a 3-Year Prospective Phase III Clinical Trial of Oral Toremifene

PURPOSE To reassess the clinical and biologic significance of myeloid-associated antigen expression in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS We prospectively studied 334 newly diagnosed cases of this disease, using a comprehensive panel of antibodies that represented five myeloid cluster groups (CD13, CD14, CD15, CD33, and CD65). Blast cells were tested for ETV6 and MLL rearrangement using Southern blot analysis. RESULTS CD13 was expressed in 13.7% of cases, CD14 in 1%, CD15 in 6.6%, CD33 in 16%, and CD65 in 9.7%. Approximately one third of cases (31.4%) expressed one or more of these antigens (B-cell precursor, 31.9%; T-cell, 28.8%), while 10.5% expressed two or more (B-cell precursor, 11.3%; T-cell, 6.1%). Among the B-cell precursor leukemias, myeloid-associated antigen expression was significantly associated with a lack of hyperdiploidy and rearrangements of ETV6 or MLL gene. Most of the cases with MLL rearrangements (82%) expressed CD65, CD15, and CD33, either alone or in combination, whereas 48% of those with a rearranged ETV6 gene expressed CD13, CD33, or both. Myeloid-associated antigen expression did not correlate with event-free survival, whether the analysis was based on any of the five antigens in our panel or on the three more commonly tested antigens (CD13, CD33, and CD65). Importantly, this finding was not affected by exclusion of patients with ETV6 or MLL gene rearrangements. CONCLUSION Even though blast cell expression of myeloid-associated antigen expression shows significant associations with specific genetic abnormalities, it lacks prognostic value in childhood ALL.